Breast cancer is a multi-faceted disease that is influenced by many factors including genetics, as well as endo- genous and exogenous environmental factors that affects a significant number of women worldwide. We are interested in determining the environmental agents that influence the course of this disease and how these environmental factors interplay with products of breast cancer susceptibility genes. We are specifically investigating the function of the breast and ovarian susceptibility gene, BRCA1. We have found that decreased expression of BRCA1 using antisense cDNA results in an increase in tumorigenicity and anchorage-independence, as well as a growth advantage in normal growth restrictive conditions, such as low estrogen in ovarian cancer cells. In addition, loss of BRCA1 may result in resistance to apoptotic stimuli induced by hydrogen peroxide. We have succeeded in expressing exogenous BRCA1 in cells using a genomic TAR expression vector. The advantage of this system is that the typical toxicity that is observed with BRCA1 overexpression does not occur. In addition, BRCA1 expression is modulated similar to the endogenous gene as was demonstrated by maintenance of serum inducibility of expression. Finally, the role of the IGFI and the progression of breast carcinoma is being investigated. We have shown that decreased activation of the IGF pathway by treatment of cells with the soluble IGFIR results in a significant decrease of invasion potential and metastases of the breast cell line, MDAMB435. This will be the final year for this project, the components of this project will be continued in a new project in the Gene Regulation Group AND in current project # ES-23003 in FY 00. - BRCA1, BRCA2, metastasis, IGFI, apoptosis, estrogen